Erectile dysfunction, defined as the persistent inability to maintain an erection sufficient for satisfactory sexual performance, affects millions of men worldwide. The conventional treatment for ED is administration of a PDE-5 inhibitor, such as sildenafil, vardenafil or tadalafil. However, a significant percentage of subjects receiving PDE-5 inhibitors do not respond adequately. Approximately 30% to 50% of men receiving sildenafil, for example, do not adequately respond to therapy, such that other therapeutic options for the treatment of ED are desirable.
The reasons that some subjects do not respond to treatment with PDE-5 inhibitors are not completely known. Clearly, testosterone plays a role in ED, and may impact a subject's response to conventional ED treatment. Studies conducted in which testosterone is co-administered to ED subjects in combination with a PDE-5 inhibitor suggest that raising the testosterone level in certain individuals may improve their response to conventional ED treatment. However, testosterone treatment is associated with undesirable side effects, including prostate stimulation, gynecomastia, and adverse effects on lipid metabolism.
Thus, it further would be desirable to provide a medicine that can be co-administered with a PDE-5 inhibitor, having the effect of raising testosterone levels and improving response to ED treatment, with fewer of the deleterious side effects of exogenous testosterone treatment.
Men with chronic obstructive pulmonary disorder (COPD), HIV-infected men, and men with metabolic syndrome experience muscle wasting and low testosterone. In one study, low testosterone was observed in subjects with diabetes mellitus who failed conventional ED treatment, and some improvement was noted when the subjects were treated with testosterone together with VIAGRA® (sildenafil citrate). Muscle wasting in HIV-infected men having low testosterone was ameliorated with a combined regimen of testosterone and exercise. Thus, it further would be desirable to develop ED treatments for these individuals, which at the same time would address the concomitant problems of muscle wasting and ED.
As disclosed in U.S. Published Patent Application No. 2006/0293294, which is incorporated herein by reference, selective estrogen receptor modulators (SERMs) have been suggested as a treatment for androgen deficiency in males.
It is believed that fispemifene, which is a SERM that acts as an estrogen antagonist, as a result of its unique properties and mechanism of action, holds special attractiveness as a treatment for ED, alone or in combination with other therapies. Fispemifene, which is the generic name for (Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol, is a selective estrogen receptor modulator having both estrogen-like and antiestrogenic properties. Fispemifene has been shown clinically to increase serum testosterone levels in males, as described in the aforesaid U.S. Published Patent Application No. 2006/0293294, and is the most preferred agent for use in combination with a PDE-5 inhibitor, as disclosed herein.
It is believed that fispemifene acts as an antiestrogen at the level of the hypothalamic-pituitary axis, diminishing the negative feedback of estrogen, which results in the enhanced production of luteinizing hormone (LH) resulting in a subsequent increase in testosterone levels.
Based on the foregoing, fispemifene is herein proposed as a treatment for ED, alone or as adjuvant therapy with other medications. Fispemifene may be especially useful in the treatment of erectile dysfunction in men having low testosterone, as a result of age or disease condition.
Ospemifene (2-(4-((Z-4-chloro-1,2-diphenylbut-1-enyl)phenoxy) ethanol)) is a SERM which may be administered in combination with conventional ED treatment according to the present invention. Suitable forms and dosage amounts of ospemifene are disclosed in U.S. Pat. No. 5,750,576, which is incorporated herein by reference.
Clomifene (N-[2-[4-(2-chloro-1,2-diphenyl-ethenyl)phenoxy]ethyl]-N-ethyl-ethanamine) (mixture of cis- and trans-isomers) and enclomifene (trans-clomifene, or a mixture in which trans-clomifene predominates), have been proposed as agents for increasing testosterone levels. U.S. Published Patent Application No. 2004/0097597, which is incorporated by reference, proposes a dosage of trans-clomifene of about 1 to about 200 mg to increase serum testosterone, and the connection between low testosterone level and erectile dysfunction is noted, although treatment of ED per se, alone or in combination with a PDE-5 inhibitor, is not disclosed in that application.
Based on the foregoing, clomifene or enclomifene are also proposed as a combination therapy with a PDE-5 inhibitor for treatment of ED.